Abstract In fatal Lassa fever (LF), an unchecked viremia leads to progressive signs and symptoms of hemorrhagic disease and shock. Since death occurs in the absence of extensive inflammation and tissue destruction, the fatal disease is most likely caused by virus-induced changes in host cell function, rather than by immunopathology. The molecular analysis of the virus-host cell interaction is therefore of great importance to understand the mechanisms of the disease and for the development of novel therapeutic strategies to treat critically ill patients. The interaction of a virus with its cellular receptors is a fundamental aspect of the virus-host cell relationship and a key determinant for the tissue tropism and the disease potential of a virus. Based on its pivotal importance for normal cell homeostasis and function, the cellular receptor of Lassa fever virus (LFV), alpha-dystroglycan (alpha-DG), is of particular interest regarding virus-induced cytopathology. In the host cell, atpha-DG provides an essential molecular link between the extracellular matrix (ECM) and the cytoskeleton. The glycoprotein (GP) of LFV binds alpha-DG with high affinity and efficiently competes with the interaction of alpha-DG with ECM proteins. Binding of LFVGP therefore likely interferes with the normal function of this important cellular receptor, contributing to virus-induced host cell dysfunction. Using a combination of biochemical and cell biological techniques, our study aims at the identification of alpha-DG-associated host cell proteins whose interactions, activation states, and cellular localization are changed by LFVGP binding. Since alpha-DG and its known binding partners are ubiquitously expressed cellular proteins, candidates identified by our study represent likely crucial targets of LFV critically involved in the pathogenesis of fatal LF. alpha-DG-associated proteins and signaling pathways that are affected by LFVGP will therefore be evaluated as potential targets for anti-viral therapy.